PB1918: MOLECULAR CHARACTERIZATION AND CLINICAL RELEVANCE OF ERYTHROPOIESIS IN MIELODYSPLASTIC SYNDROMES.
Authors: A. Villalba, E. Such, L. Senent, E. Mora, G. Avetisyan, A. I. Vicente, M. Tormo, A. Jerez, F. Ramos, J. Montoro, T. Bernal, I. lLuna, M. Santiago, A. Diaz, A. Liquori, J. Cervera, G. Sanz
Journal: HemaSphere (2022)

Background: The prognostic relevance of the percentage of erythroid precursors in Myelodysplastic Syndromes (MDS) and its relationship with other clinic-biological characteristics remains largely unknown. Some studies support that the presence of more than 50% and less than 15% of erythroid precursors (EPs) in bone marrow (BM) is a poor prognostic factor in MDS for long-term outcomes. In those cases, a higher frequency of complex karyotypes and monosomies have been observed but the mutational profile associated with the percentage of EPs remains largely unknown. Aims: Our main aim was to analyze the biological and clinical features of MDS patients according to the percentage of EPs in BM and mutational profile at the time of diagnosis to evaluate its prognostic value on overall survival (OS) and to better understanding the molecular pathogenesis of these disorders. Methods: We retrospectively analyzed 133 de novo MDS patients from the MDS Spanish Registry. All patients were categorized into two groups according to the percentage of EPs in BM: ≤15% and ≥15%. The molecular study by NGS of the BM samples was performed using MYS (Myeloid SolutionTM) from SOPHiA Genetics. All mutations selected were categorized as benign, likely benign, variant of uncertain significance (VUS), likely pathogenic, or pathogenic by following the “Standards and guidelines for the interpretation of sequence variants” from the American College of Medical Genetics and Genomics. Information from biological databases and in silico was considered. All statistical analysis were performed by the R software. Results: In Table 1 are displayed the clinical and biological characteristics statistically significant in both groups. The mutation study showed that the most frequently mutated genes in the total series were SF3B1, which was altered in 39 of the cases analyzed (29%), TET2 in a total of 35 patients (26%) and ASXL1 in 34 patients (26%). Patients with ≤ 15% of EPs showed a statistically significant lower frequency of mutations in SF3B1 (11% vs. 41%; p< 0.001), higher frequency of mutations in DNMT3A (26% vs. 6%; p = 0.003) and increased number of mutations in NRAS (15% vs. 1%; p = 0.003). Patients with ≤ 15% of EPs in BM had a higher frequency of mutations in the signal transduction gene group (5% vs 2%; p = 0.013). The ≤15% EPs group showed a markedly inferior OS (median OS, 24 months versus 69 months in the group with >15% EPs; p < 0.001). However, there were no clear differences between both groups in the risk of transformation to AML. In the multivariate analysis the ≤ 15% of EP group was an independent risk factor on global survival (p = 0,003), as well as, R-IPSS (p = 0.008) and mutations in RUNX1 (p = 0.042), ASXL (p = 0.004) and TP53 (p = 0.005). Table 1. - ≤15% of EP > 15% of EP p N patients (%) 80 (60%) 53 (40%) Blast in BM >10% 26% 15% p = 0.014 SF3B1 mutation 11% 41% P < 0.001 Frequency DNMT3A mutations 26% 6% p = 0.003 Frequency NRAS mutations 15% 1% p = 0.003 Signal transduction mutations (NRAS, KRAS, JAK2, MPL, PTPN11, NF1, CBL ) 5% 2% p = 0.013 DNA methylation mutations (TET2, NDMT3A, IDH1, IDH2 ) 17% 10% P = 0.037 Transfusion dependence 63% 41% P = 0.037 Azacitidine tretatment 43% 26% p = 0.002 Deaths 68% 40% p = 0.003 OS 24 moths 69 moths p < 0.001 Summary/Conclusion: Our study confirms the prognostic impact of EPs percentage in BM on OS and demonstrate notable differences in their mutational profile.